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  1. Article ; Online: Molecular and Metabolic Analysis of Arsenic-Exposed Humanized AS3MT Mice.

    Todero, Jenna / Douillet, Christelle / Shumway, Alexandria J / Koller, Beverly H / Kanke, Matt / Phuong, Daryl J / Stýblo, Miroslav / Sethupathy, Praveen

    Environmental health perspectives

    2023  Volume 131, Issue 12, Page(s) 127021

    Abstract: Background: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a ... ...

    Abstract Background: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new "humanized" mouse model overcomes this limitation. In this study, we leveraged this model to study sex differences in the context of iAs exposure.
    Objectives: The aim of this study was to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure.
    Methods: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic
    Results: We detected sex divergence in liver and adipose markers of diabetes (e.g., miR-34a, insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice.
    Discussion: Our study underscored the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings suggested that humanized males are at increased risk for metabolic dysfunction relative to humanized females in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence. https://doi.org/10.1289/EHP12785.
    MeSH term(s) Female ; Male ; Mice ; Humans ; Animals ; Arsenic/analysis ; Blood Glucose/analysis ; Diabetes Mellitus, Type 2/chemically induced ; Arsenicals ; Insulin Resistance ; Insulin ; Obesity ; Methyltransferases/genetics
    Chemical Substances Arsenic (N712M78A8G) ; Blood Glucose ; Arsenicals ; Insulin ; AS3MT protein, human (EC 2.1.1.137) ; Methyltransferases (EC 2.1.1.-) ; AS3MT protein, mouse (EC 2.1.1.137)
    Language English
    Publishing date 2023-12-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 195189-0
    ISSN 1552-9924 ; 0091-6765 ; 1078-0475
    ISSN (online) 1552-9924
    ISSN 0091-6765 ; 1078-0475
    DOI 10.1289/EHP12785
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.

    Ma, Rosanna K / Tsai, Pei-Yin / Farghli, Alaa R / Shumway, Alexandria / Kanke, Matt / Gordan, John D / Gujral, Taranjit S / Vakili, Khashayar / Nukaya, Manabu / Noetzli, Leila / Ronnekleiv-Kelly, Sean / Broom, Wendy / Barrow, Joeva / Sethupathy, Praveen

    PLoS genetics

    2024  Volume 20, Issue 3, Page(s) e1011216

    Abstract: Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene ... ...

    Abstract Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.
    MeSH term(s) Adolescent ; Humans ; Young Adult ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics ; HSP40 Heat-Shock Proteins/genetics ; HSP40 Heat-Shock Proteins/metabolism ; Liver Neoplasms/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
    Chemical Substances Cyclic AMP-Dependent Protein Kinase Catalytic Subunits (EC 2.7.11.11) ; DNAJB1 protein, human ; HSP40 Heat-Shock Proteins ; PRKACA protein, human (EC 2.7.11.11) ; RNA, Long Noncoding ; LINC00473 RNA, human
    Language English
    Publishing date 2024-03-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1011216
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Linking gene expression to clinical outcomes in pediatric Crohn's disease using machine learning.

    Chen, Kevin A / Nishiyama, Nina C / Kennedy Ng, Meaghan M / Shumway, Alexandria / Joisa, Chinmaya U / Schaner, Matthew R / Lian, Grace / Beasley, Caroline / Zhu, Lee-Ching / Bantumilli, Surekha / Kapadia, Muneera R / Gomez, Shawn M / Furey, Terrence S / Sheikh, Shehzad Z

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 2667

    Abstract: Pediatric Crohn's disease (CD) is characterized by a severe disease course with frequent complications. We sought to apply machine learning-based models to predict risk of developing future complications in pediatric CD using ileal and colonic gene ... ...

    Abstract Pediatric Crohn's disease (CD) is characterized by a severe disease course with frequent complications. We sought to apply machine learning-based models to predict risk of developing future complications in pediatric CD using ileal and colonic gene expression. Gene expression data was generated from 101 formalin-fixed, paraffin-embedded (FFPE) ileal and colonic biopsies obtained from treatment-naïve CD patients and controls. Clinical outcomes including development of strictures or fistulas and progression to surgery were analyzed using differential expression and modeled using machine learning. Differential expression analysis revealed downregulation of pathways related to inflammation and extra-cellular matrix production in patients with strictures. Machine learning-based models were able to incorporate colonic gene expression and clinical characteristics to predict outcomes with high accuracy. Models showed an area under the receiver operating characteristic curve (AUROC) of 0.84 for strictures, 0.83 for remission, and 0.75 for surgery. Genes with potential prognostic importance for strictures (REG1A, MMP3, and DUOX2) were not identified in single gene differential analysis but were found to have strong contributions to predictive models. Our findings in FFPE tissue support the importance of colonic gene expression and the potential for machine learning-based models in predicting outcomes for pediatric CD.
    MeSH term(s) Child ; Humans ; Constriction, Pathologic ; Crohn Disease/pathology ; Gene Expression ; Machine Learning ; Lithostathine/genetics
    Chemical Substances REG1A protein, human ; Lithostathine
    Language English
    Publishing date 2024-02-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-52678-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Aberrant miR-29 is a predictive feature of severe phenotypes in pediatric Crohn's disease.

    Shumway, Alexandria J / Shanahan, Michael T / Hollville, Emilie / Chen, Kevin / Beasley, Caroline / Villanueva, Jonathan W / Albert, Sara / Lian, Grace / Cure, Moises R / Schaner, Matthew / Zhu, Lee-Ching / Bantumilli, Surekha / Deshmukh, Mohanish / Furey, Terrence S / Sheikh, Shehzad Z / Sethupathy, Praveen

    JCI insight

    2024  Volume 9, Issue 4

    Abstract: Crohn's disease (CD) is a chronic inflammatory gut disorder. Molecular mechanisms underlying the clinical heterogeneity of CD remain poorly understood. MicroRNAs (miRNAs) are important regulators of gut physiology, and several have been implicated in the ...

    Abstract Crohn's disease (CD) is a chronic inflammatory gut disorder. Molecular mechanisms underlying the clinical heterogeneity of CD remain poorly understood. MicroRNAs (miRNAs) are important regulators of gut physiology, and several have been implicated in the pathogenesis of adult CD. However, there is a dearth of large-scale miRNA studies for pediatric CD. We hypothesized that specific miRNAs uniquely mark pediatric CD. We performed small RNA-Seq of patient-matched colon and ileum biopsies from treatment-naive pediatric patients with CD (n = 169) and a control cohort (n = 108). Comprehensive miRNA analysis revealed 58 miRNAs altered in pediatric CD. Notably, multinomial logistic regression analysis revealed that index levels of ileal miR-29 are strongly predictive of severe inflammation and stricturing. Transcriptomic analyses of transgenic mice overexpressing miR-29 show a significant reduction of the tight junction protein gene Pmp22 and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we found that pediatric patients with CD with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels of PMP22. These findings strongly indicate that miR-29 upregulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.
    MeSH term(s) Adult ; Animals ; Mice ; Humans ; Child ; Crohn Disease/pathology ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Phenotype ; Inflammation
    Chemical Substances MicroRNAs ; MIRN29 microRNA, mouse
    Language English
    Publishing date 2024-02-22
    Publishing country United States
    Document type Journal Article
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.168800
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: SELfies and CELLfies: Whole Genome Sequencing and Annotation of Five Antibiotic Resistant Bacteria Isolated from the Surfaces of Smartphones, An Inquiry Based Laboratory Exercise in a Genomics Undergraduate Course at the Rochester Institute of Technology.

    Parthasarathy, Anutthaman / Wong, Narayan H / Weiss, Amanda N / Tian, Susan / Ali, Sara E / Cavanaugh, Nicole T / Chinsky, Tyler M / Cramer, Chelsea E / Gupta, Aditya / Jha, Rakshanda / Johnson, Loryn K / Tuason, Elizabeth D / Klafehn, Lauren M / Krishnadas, Varada / Musich, Ryan J / Pfaff, Jennifer M / Richman, Spencer C / Shumway, Alexandria J / Hudson, André O

    Journal of genomics

    2019  Volume 7, Page(s) 26–30

    Abstract: Are touchscreen devices a public health risk for the transmission of pathogenic bacteria, especially those that are resistant to antibiotics? To investigate this, we embarked on a project aimed at isolating and identifying bacteria that are resistant to ... ...

    Abstract Are touchscreen devices a public health risk for the transmission of pathogenic bacteria, especially those that are resistant to antibiotics? To investigate this, we embarked on a project aimed at isolating and identifying bacteria that are resistant to antibiotics from the screens of smartphones. Touchscreen devices have become ubiquitous in society, and it is important to evaluate the potential risks they pose towards public health, especially as it pertains to the harboring and transmission of pathogenic bacteria that are resistant to antibiotics. Sixteen bacteria were initially isolated of which five were unique (four
    Language English
    Publishing date 2019-02-19
    Publishing country Australia
    Document type Journal Article
    ZDB-ID 2692697-0
    ISSN 1839-9940
    ISSN 1839-9940
    DOI 10.7150/jgen.31911
    Database MEDical Literature Analysis and Retrieval System OnLINE

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